Substituted azacycloalkanes



7 amino and mono and di-lower alkyl-substituted amino rad- 2,740,779 Patented Apr. 3, 1956 nesium halide is prepared from 0.070 g-atom of magnesium 2 740 779 metal and 0.075 mole of alkyl halide in 100 ml. of dry ether. To this solution is added dropwise 0.05 mole of SUBSTITUTED AZACYCLOALKANES the appropriate 4-cyano compound in 100 ml. of toluene.

5 D Julius Diamond Philadelphia and William F. Bruce, The temperature 1sma1nta1ned,w1thst1rr1ng, at 25 35 C during the addition. On its completion, the temperature is gggg gzgafgfasfi ggflf ?t g gg gfififi Egg gradually raised by distilling off the ether. A maximum ware temperature of 65-85 C. is maintained for 6 hours. The mixture is cooled and extracted with dilute hydrochloric N0 gl p January 5, 1954, 10 acid. The acid extract is washed with ether, then basisenal 402,397 fied with ammonium hydroxide, and finally extracted with 2 Claims (C1. z chloroform. The chloroform extract is dried over anhydrous sodium sulfate, filtered, and concentrated. Vacuum distillation of the residue gives the desired aminoketone This invention relates to the preparation of cyclic comhas?" PoundS and more Particularly the Preparation of y Acid addition salts of the cyclic bases may be made in Ycloalkanes. well known manner as disclosed in Application Serial No.

The compounds falling with the scope of the invention 297,185 by reacting the appropriate base with the desired are specific members of the more general group of cominorganic or organic carboxylic acid. Preferred acids are pounds and claimed in application Serial No. 297,185, filed those mentioned in said prior application These cyclic July 3, 1952. The present compounds may be represented bases fi also callable of reacting alkyl halides On by the general f l an equlmolar basis under normal conditions to form quaternary ammonium compounds.

O The reaction is carried out in the prsence of inert solvent.

H I For a more specific description of the process, the following reactions illustrate the formation of the specific compound 4-propionyl-4-m-hydroxyphenyl-l-methylaza- CHPC cylcoheptane. (IN ON rn-CH3OCH -CHCH;CH5N(CH:)2 NaNH m-CH3OCsH4( JCH CHzN(CH;)z CQHgCN ether 100 BYCHCHQCHQC! HgCHnCHr-Cl CN OH HI CHHO CUHA (IJCHQCHQ CH3 m-CHCQH4J)-CH2CH 200250 EtMgBr N 01- GE; 3 mm ether HgCHgC 9 CH; CHCHIO a (III) COCHQCH; COCHzCHa m-CHaO-CsHr CHICHQ HB m-HOCuHr- -CH&CH2

I NCH: NCHa CHQCHQCQQ H2CH2CH2 wherein X stands for either N-R1 or 4-cyano-4-m-methoxyphenyl-N-methylazacycloheptane /R methochloride (Compound ll).

N-A A solution of 0.181 mole (39.5 g.) of Z-(m-methoxyphenyl)-4-dimethylamino-butyronitrile in 250 ml. of ether was added to a stirred suspension of 0.217 mole (8.5 g.) of sodamide in 250 ml. of other at such a rate as to maintain gentle refluxing. The operations were carried out in a nitrogen atmosphere. Refluxing and stirring were contined for 2 additional hours. The mixture was cooled to 30 C., and 0.199 mole (31.5 g.) of trimethylene chlorobromide in 100 ml. of ether was added dropwise at 25 C. to --15 C. while stirring. The mixture was then allowed to warm to room temperature and stand overnight The precipitated inorganic salts were filtered off and the ether distilled from the filtrate at reduced pressure. The yellow liquid residue contained the 1,6-amino-chloride (I) with R1 representing a lower alkyl and R2 standing for either hydrogen or an alkyl while A is an anion, R standing for an aryl group and with R3 and R4 each standing for hydrogen or lower alkyl and R5 representing a lower alkyl group.

With regard to R which represents an aryl radical, the latter may be either a subtituted or unsubstituted phenyl ring. Preferred substituents on a ring which may be in any position and ranging from 1 to 3 are lower alkyl, lower alkoxy, halogen, nitro, hydroxy, aliphatic acyl and acyloxy,

icals. As will be indicated later, an especially preferred radical because it imparts valuable therapeutic action to 6 i was diisolved m 180 of benzonitrfle and the i the compound is the m hydroxy phenyl radicaL In 5 sulting solution heated at C. for 20 hours. The mixeral, the compounds of the invention may b d in the ture was cooled, ml. of acetone added, and the premanner disclosed in the earlier filed application Serial cipitated quaternary salt (H) was filtered 05 after Stand- No. 297,185. A general procedure for making specific ing 4 hOuIS- 4-acyl compounds utilizes the cyano compound obtained 70 for C16H23C1N20; from Reaction 3 disclosed in said earlier case. In such N, 9.51; C1, 12 Found; N, general procedure, an ether solution of the alkyl mag- Cl, 12.18.

4 cyan-4 m-meth0xyphenyl-N-methylazacycloheptane (Compound III) Into a small Claisen flask setup for distillation, was placed 0,085 mole (25 g.) of the quaternary salt (II).

4 with chloroform. The extract was dried, filtered, and distilled. At 190-2Q0 C. (0.3 mm.) 3.3 g. of a yellow viscous syrup distilled over. On cooling the material became glassy. It was dissolved in boiling ether, filtered,

Aft'erevacuatingthe systemyto 1--3 mm., heat'wa'sta'pplied 5 and t filtrate concentrated a small volume on useing an air-bath. At a bath temperature (if-"200450" standlpg tempera-me the P? duct. (V) appeared c. a liquid distilled over at 170-210 c. Redis'tillation. as Whlte .qystals- Thermlxmre l crystal? gave the 'cyano base (III), B. P.3l5'0- -154" C. (0.3 mm.'), Washed with r ii i ai li 1 1 nbzg 153.352 2.422 1.062. tpurple color with aqueousmlcohohcternc chloride S0l110l'1. jgf gff fgg gfiflfig; gjg gi fi' f gg Anal.-Calcd. for C16H2NO22 c, 73150; H, 8.86; 'N, 5.36. Found: C, 73.92; H, 9.05; N, 5.53.

D I Other compounds falling within the scope of the inven- -1 i y -m yp n m wy tion are given in the'following table with identifying charheptlme p acteristics. The various radials .R,-R3, R4 and R5 are vEthyl magmas-Him bromide was .pwpare-d from specific species of the general "formula given hereinbelow. g-ato'm (-2.2 g.) of magnesium metal and 0.10 mole RFCO R (10.9 g.) of ethyl bromide in 150 ml. ether. To this solu- I I don was added, with stirring, 0.0573 mole -14 g.) or the f' E cyano'b'ase (III) in 150 ml. of ether at such a rate as 20 to maintain gentle refluxing. After 5 additional hours R Ra R4 R5 3 nn( 0.) Derivative, M. P.

- 0.11. a H 2 i 1180MB) ifil fii fidiflii 'cim H H, 11-03111 132-3 1. 5300 (26) i plcrate,13840. 0 11i H OH; 2H 135-42 1.'5350(-27.'5) methlodide, 183-5". .C Hs CH3 H C H 13342 1. 5400 (27) 3 pierate,1645 d.

of stirring and refluxing, the mixture was allowed to stand The cyclic free bases 'are useful for the formation of overnight. The cooled mixture was extracted with aquequaternary ammonium compounds since they readily reous hydrochloric acid, the acid extract basified with amact with an alkyl halide, particularly the long chain alkyl monium hydroxide, extracted with ether, and the "ether halides, to form valuable wetting'a'gents. These bases 'or extract dried, filtered, and concentrated under reduced their acid-addition'salts are also capable of reacting with pressure. A light yellow liquid residue remained which penicillin to form substantially water-insoluble salts contained the crude ketobase (IV). thereof. In addition, many of the bases or their salts demonstrate varying degrees of analgesic action and thus 4-propzanyl-4-m-hydroxyphenyl-methylazacycloheptane are useful .therapeutics (Compound V) 40 We claim:

The above compound (IV) was usedwithout further The compound 12'd1methy1'4'phenyl'4'proplonyl purification. It was dissolved in T00 ml. of 48% hydroazacycloheptane' bromic acid. The solution was heated to reflux and kept A compoufld of the group conslstmg of 12'd1methy1' at this temperature (110425.. a) for 17 The 4-phenyl-4-prop1onyl azacycloheptane and salts thereof.

cooled solution was treated with 230 ml. of 4.N-'sodi-um hydroxide solution and the resultingfsolution washed with ether. The aqueous alkaline solution was saturated with carbon dioxide to precipitate an oil which was extracted References Cited in the file of this patent UNITED STATES PATENTS 2,666,050 Diamond et al. Jan. 12, 1954 

2. A COMPOUND OF THE GROUP CONSISTING OF 1,2-DIMETHYL4-PHENYL-4-PROPIONYL AZACYCLOHEPTANE AND SALTS THEREOF. 